Gender-Based Differences in Cardiac Repolarization in Mouse Ventricle

Abstract

The mouse heart has become a widely used model for genetic studies of heart diseases. Thus, understanding gender differences in mouse cardiac repolarization is crucial to the interpretation of such studies. The objective of this study was to evaluate whether there are gender differences in cardiac repolarization in mouse ventricle and to gain insights into the ionic and molecular mechanisms underlying these differences. Action potential durations (APDs) and K(+) currents in male and female ventricular myocytes were compared using a patch-clamp technique. APD(20), APD(50), and APD(90) were found to be significantly longer in females than males. Examination of the different K(+) currents revealed that a significantly lower current density exists in female ventricular myocytes compared with male myocytes for the ultrarapid delayed rectifier K(+) current, I(Kur) (at +30 mV, male, 33.2+/-2.9 pA/pF [n= 22]; female, 20.9+/-1.73 pA/pF [n= 19], P<0.001). Consistent with these findings were the results of the ribonuclease protection assay, Western blots, and confocal analysis that showed a significantly lower expression level of Kv1.5 (coding for I(Kur)) in female compared with male ventricle. The additional K(+) currents present in mouse ventricle exhibited no gender differences. In agreement with these electrophysiological data, no differences in the expression levels for the K(+) channels underlying these currents were detected between both sexes. This study demonstrates that adult mice exhibit gender differences in cardiac repolarization. The expression of Kv1.5 and of its corresponding K(+) current, I(Kur), is significantly lower in female mouse ventricle, and as a result, the APD is lengthened.

Female Mice Lacking Estrogen Receptor β Display Prolonged Ventricular Repolarization and Reduced Ventricular Automaticity After Myocardial Infarction

“…13,34 We showed a decreased expression of Kv4.3 (coding for I to ) in the ␤ERKO left ventricle but not in the ␣ERKO left ventricle. The expression of Kv1.5 was unchanged in both ␣ERKO and ␤ERKO animals.…”

“…We chose these channels because earlier reports suggest that the expression and function of these 2 potassium channels are likely to be dependent on the sex hormone receptor status (ie, estrogen receptors). 13,34 Whereas the transcript levels of Kv1.5 showed no significant difference, there was a significantly lower expression (PϽ0.05) of Kv4.3 in ␤ERKO mice ( Figure 5). These data are consistent with our electrophysiological data because decreased expression of Kv4.3 in female ␤ERKO mice could explain the significant prolongation of repolarization and altered ventricular automaticity in the infarcted animals with knockout of ER␤.…”

“…[45][46][47][48][49] However, the results of animal studies with regard to the electrophysiological effects of sex hormones have been divergent, and it is not clear from previous data whether sex steroid hormones consistently alter cardiac repolarization. 50 -52 Trepanier-Boulay et al 13 found a significantly prolonged ventricular repolarization as measured by action potential duration in female mice compared with male mice, which was accompanied by a significantly decreased expression of Kv1.5 and of its corresponding K ϩ current, I kur , in the female ventricle. Saba et al 22 found that 17␤-estradiol prolongs AV nodal conduction and the right ventricular effective period, and they argue that hormonal status affects aspects of cardiac electrophysiological function.…”

Gender Disparities in Cardiac Cellular Electrophysiology and Arrhythmia Susceptibility in Human Failing Ventricular Myocytes

“…However, our findings are in agreement with studies in healthy animals. Female APs are significantly longer than male APs in mouse subepicardial VMs, 27,28) rabbit left ventricular subendocardial VMs, 29) dog left ventricular midmyocardial VMs, 30) and guinea pig right and left ventricular VMs at the day of estrus. 31) Furthermore, our findings are in accordance with the clinical observation that women have longer QTc intervals.…”

Gender disparities in torsade de pointes ventricular tachycardia

“…12 I to in females is 0.75 times that of males in all cell layers, 13,14 although this is not a consistent finding. 15,16 I Kr in females is 0.83 times that of males. 17 These gender disparities were incorporated into the PB model.…”